Abstract Atopic Dermatitis (AD) is a T cell hypersensitivity skin disease and is associated with weakened skin barrier. People with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most susceptible individuals do not develop the diseases, suggesting that there exist regulatory immune mechanisms. We have developed an animal model to identify the regulatory immune circuit that prevents AD. Absence of innate IL-17+ ?? T (T??17) cells results in spontaneous AD with all major hallmarks of human AD, placing these cells as the apex regulator of skin homeostasis. In the chronic AD stage, distinct CD4+ T helper effector subsets of constrained clonotypes dominate. Skin Th17 and Th22 cells are commensal bacteria (CB)- dependent, highly restricted in T cell antigen receptor (TCR) repertoire, and some of the clonotypes are extensively expanded in normal and diseased skin. Coincidently, type 2 cytokine secreting innate lymphoid cells 2 (ILC2) expand, which sets up an amplifying autofeedback loop with T cells to chronically inflame the skin. The following model of AD progression will be tested: 1. Regulatory stage: Dermal T??17 cells and ?? T cells survey skin homeostasis and barrier integrity by monitoring dermal APCs. T??17 and Th2 cells seed the skin early in life. T??17 cells, CB and local DCs coordinately promote barrier integrity through crosstalk with keratinocytes. Meanwhile, polyclonal Th2 cells are positioned to induce an allergic response towards invading pathogens. During the colonization of skin by CB, a symbiotic immune response ensues with V?4+ CB-specific CD4+ T cells expanding and differentiating into `non-pathogenic' skin resident IL-17+ T cells. 2. Elicitation stage: When T??17 cells are compromised, the barrier is degraded over time with an attendant leakage of CB and enhanced necroptosis, leading to the release of skin antigens that activate Th2 cells, and DAMPs, the most critical being IL-33. In conjunction with TSLP released by keratinocyte under stress, IL-33 drives ILC2 expansion, which further amplifies Th2 cells. Activated ILC2 and Th2 cells, in turn unleash mast cells. Together, excess type 2 cytokine production recruits eosinophils. Some tissue-resident, Th17 cells become activated and promote neutrophil recruitment. 3. Pathogenic stage: During the acute phase, IL-17 release further recruits neutrophils and amplifies the inflammatory cascade that leads to epithelial barrier damage. Inflammation and antigen release from damaged skin activates oligoclonal T cells in the skin dLNs and/or in lesional skin sites. IL-1, IL-6, IL-23, Ahr ligands and TNF? released during inflammation induces skin-resident Th17 cells to expand and acquire a `pathogenic' dual IL-17/22+ phenotypes, whereas the emergent Th22 cells represent an immune countermeasure to repair damaged skin. By mapping central cellular interactions and molecular regulatory network in spontaneous mouse models of AD, the origin of AD and the nature of pathogenic T cells can be understood, paving the way towards identification of T cell skin antigens responsible for AD.